Formaldehyde (FA) is a ubiquitous environmental and occupational toxicant that is associated with an increasing number of human cancers. FA is also generated endogenously as a product of lipid peroxidation, drug biotransformation and several normal metabolic processes, such as histone demethylation during chromatin remodeling. Molecular mechanisms of FA carcinogenicity are poorly understood, in part reflecting its past association only with rare nasal cancers. A growing list of human cancers recently linked to FA exposure is difficult to explain by the cytotoxicity-based risk assessment models developed for nasal cancers in rodents. This application is designed to address major research gaps that hinder mechanistic understanding of FA-induced carcinogenic effects. Three specific aims are proposed to (1) determine main causes of FA mutagenicity in human cells, (2) identify genomic sites and genes that are prone to large rearrangements and (3) examine a role of epigenetic injury in the formation of large genetic changes by FA in human adult stem cells. A successful completion of these studies can lead to the identification of the mechanistically important biomarkers of genetic damage by FA and help resolve current uncertainties regarding its mode of carcinogenic action and ability to initiate leukemogenic events. PUBLIC HEALTH RELEVANCE: Formaldehyde is a ubiquitous environmental toxicant with a growing list of human cancers associated with its exposure. The molecular mechanisms underlying carcinogenic properties of formaldehyde are poorly understood, which makes it difficult to adequately assess human risks. This proposal is focused on the determination of DNA lesions that cause mutations and gross chromosomal damage in formaldehyde-exposed human cells. The completion of the proposed studies could lead to the identification of the important forms of genetic damage by formaldehyde and improve human risk assessment.